CA2632854A1 - 2-carbamide-4-phenylthiazole derivatives, preparation thereof and therapeutic use thereof - Google Patents

Abstract

The invention relates to 2-carbamide-4-phenylthiazole derivatives, following general formula (I). The subject of the invention is also pharmaceutical compositions containing a compound of general formula (I).

Description

DERIVATIVES OF 2-CARBAMIDE-4-PHENYLTHIAZOLE, THEIR PREPARATION AND
THEIR APPLICATION IN THERAPEUTICS

The invention relates to 2-carbamide-4-phenylthiazole derivatives, to their preparation and their application in therapy.

The subject of the invention is compounds corresponding to formula (I) below:
Y
SO
N ~ N'J ~ N '(CH2) P
Ri H ~ (I) N ~ R

in which :
R 1 represents a hydrogen atom, a halogen atom, a (C 1 -C 8) alkyl group, trifluoro (C1-C4) alkyl, -OH, -O- (C1-C8) alkyl, -O-trifluoro (C1-C8) alkyl, -O-(Cl C8) alkyl- (C3-C, o) cycloalkyl, -O- (C3-Clo) cycloalkyl, -O-CH2-CH = CHa, -S- (C, -C4) alkyl;
R2 represents a hydrogen atom, a halogen atom, a -OH group, C8) alkyl, trifluoro (C1-C4) alkyl, perfluoro (C1-C4) alkyl, (C3-C10) cycloalkyl, -O- (C, -C $) alkyl, -O- (C1-C4) alkyl- (C3-C10) cycloalkyl, -O- (C3-C10) cycloalkyl, -O-CH = CH 2 1 - (C 1 -C 8) alkyl- (C 3 -C 8) cycloalkyl;
Y represents a hydrogen atom or a halogen;
p represents 2 or 3;
R3 represents:

a1) a group of formula - (CH2) aA
where a represents 1, 2, 3 or 4, and A is selected from the group consisting of by:
17 R ~ ~
1 1 ' NNNO
D; ; -0; and O
where R7 is selected from the group consisting of:
= - (Cl-C8) alkyl-COO- (C, -C8) alkyl,

2 = -CO- (C1-C8) alkyl where the alkyl is substituted by at least one atom halogen, = - (C3-Clp) cycloalkyl, = phenyl, = -COO- (C3-Clo) cycloalkyl, = -SO 2 - (Cl-C 8) alkyl where the alkyl is substituted by at least one atom halogen, Is phenyl substituted with at least one -O-C8) alkyl, = -SO2-heteroaryl where the heteroaryl is a pyrazole, an isoxazole or a imidazole and where the heteroaryl is independently substituted by at least one group selected from halogen or - (C 1 -C 8) alkyl, = -SO2-N ((C1-C8) alkyl) 2, = -SO 2 -OH, = -SO2- (C3-C, o) cycloalkyl, = -CO-NH ((C 1 -C 8) alkyl), = - (C 1 -C 8) alkyl-CN, = - (Ci-C $) alkyl-imidazole, = - (C 1 -C 8) alkyl-COOH, = - (C 1 -C 8) alkyl-COO "M +, = - (Ci-C $) aikyl-OH, = - (C1-C8) alkyl-tetrazole, = - (C, -C8) alkyl-CO-NH2, = - (C 1 -C 8) alkyl-CO-NH ((C 1 -C 6) alkyl), = - (C1-C8) alkyl-CO-NH ((C3-C, o) cycloalkyl), = - (C 1 -C 8) alkyl-CO-N ((C 1 -C 8) alkyl) ((C 3 -C 10) cycloalkyl), = - (C 1 -C 8) alkyl-CO-N ((C 1 -C 8) alkyl) 2a = - (C1-C8) alkyl-CO-N ((C3-Clo) cycloalkyl) 2, where M + is an alkali metal cation selected from Li +, Na + and K +, and when there are two substituents alkyl or cycloalkyl bonded to the nitrogen atom, they can be independently identical or different;

a2) a group of formula -CO (CH2) bA
where b is 0, 1, 2, 3 or 4, and A is selected from the group consisting of by:

3 i7 i7 i7 NNNO
and O

where R7 is as previously defined;
a3) a group -B
wherein B is selected from the group consisting of:
i, I7 NSN
-CN-R ~~ ~ _D; _CO; -0; and where R7 is as previously defined;

a4) a group of formula - (CH2) ,, - C
where a represents 1, 2, 3 or 4, and C is selected from the group consisting of by:
R Rb Rc Rb 1 8 Rc Rf Rg Rf ~ \ // 0 Rg R s Ra O Rd Ra N Rd Re s Rh Re s Rh ; ; yf and or :
- R8 is selected from the group consisting of:
= a hydrogen atom, = a (Cl-C8) alkyl group, = - (C 1 -C 8) alkyl-COO- (C 1 -C 6) alkyl, = -CO- (C1-C8) alkyl wherein the alkyl is optionally substituted by at least one halogen atom, = - (C3-Clp) cycloalkyl, = phenyl, = -COO- (C3-C, p) cycloalkyl, = -SO2- (C1-C8) alkyl wherein the alkyl is optionally substituted by at least one halogen atom, = -SO2-phenyl where the phenyl is optionally substituted by at least one -O- (Cl-C8) alkyl group, = -SO2-heteroaryl where the heteroaryl is a pyrazole, an isoxazole or a imidazole and where the heteroaryl is optionally independently substituted by at least one group chosen from halogen or - (C 1 -C 8) alkyl, WO 2007/07739

4 PCT / FR2007 / 000007 = -SO 2 -N ((C 1 -C 8) alkyl) 2, = -SO 2 -OH, = -SO2- (C3-Clo) cycloalkyl, = -CO-NH ((C 1 -C 8) alkyl), = - (Cl-C8) alkyl-CN, = - (C, -C8) alkyl-imidazole, = - (C, -C8) alkyl-COOH, = - (C, -Cg) alkyl-COO "M +, = - (C 1 -C 8) alkyl-OH, = - (Ci-Ca) alkyl-tetrazole, = - (C 1 -C 8) alkyl-CO-NH 2, = - (C, -C $) alkyl-CO-NH ((C 1 -C 8) alkyl), = - (C1-C8) alkyl-CO-NH ((C3-Clo) cycloalkyl), = - (C1-C8) alkyl-CO-N ((C1-C8) alkyl) ((C3-Clo) cycloalkyl), = - (C, -C8) alkyl-CO-N ((CI-Ca) alkyl) 2, = - (C, -C8) alkyl-CO-N ((C3-ClO) cycloalkyl) 2, where M + is an alkali metal cation selected from Li +, Na + and K +, and when there are two substituents alkyl or cycloalkyl bonded to the nitrogen atom, they can be independently identical or different;
R9 is selected from the group consisting of: hydroxyl, O- (C, -C8) alkyl, -O-trifluoro (C 1 -C 6) alkyl, -O- (C 1 -C 8) alkyl- (C 3 -C 4) cycloalkyl, -O- (C 3 -C
C10) cycloalkyl, Ra, Rb, Rc and Rd are independently a hydrogen atom or a group methyl, since at least one of Ra, Rb, Rc and Rd is a group methyl;
- Re, Rf, Rg and Rh are independently a hydrogen atom or a group methyl;

a5) a group of formula -CO (CH2) bC
where b is 0, 1, 2, 3 or 4, and C is selected from the group consisting of by :
R
Rb Rc Rb 1 e Rc Rf Rg Rf 00 Rg R
Ra O Rd Ra Rd Rd Rh Rh Re Rh , and or:
R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are as defined above, a6) a group -D

wherein D is selected from the group consisting of:
R Rb Rc Rb 1 e Rc Rf Rg Rf ~ \ /% R R
Ra Rd Ra N Rd Re s Rh Re s Rh and or .
R8, R9, Ra, Rb, Rc, Rd Re, Rf, Rg and Rh are as defined previously,

5 to the basic state or acid addition salt, as well as to the state of hydrates or solvates.

A preferred halogen is a fluorine.

The compounds of formula (I) can comprise one or more atoms of carbon asymmetrical. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases or salts addition to acids. Such addition salts are part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids acceptable but the salts of other useful acids, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
The compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or several molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
In the context of the present invention, the following terms mean:
- Ct_Z where t and z can take values from 1 to 10, a carbon chain may have from t to z carbon atoms, for example C1_3 a carbon chain which may have from 1 to 3 carbon atoms;
a halogen atom is, for example, a fluorine, a chlorine, a bromine or an iodine ;
an alkyl group: a linear or branched saturated aliphatic group, optionally substituted with a halogen atom. As examples, we can to quote methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl pentyl, 2-fluoroethyl, etc .;
a cycloalkyl group: a cyclic alkyl group. As examples, we can

6 mention cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc .;
a perfluoroalkyl group: an alkyl radical, as defined previously, for which all the carbon atoms are substituted by fluorine atoms.

Among the compounds that are the subject of the invention, mention may in particular be made of the compounds of following formula:

there ISNO
\ ~
NOT
RIN
H

'R

(Ia) where R 1, R 2, R 3 and Y are as previously defined.
Preferred compounds of the invention of the formula (La) preferred are those in which R is in the 2-position and R2 is in the 5-position of the phenyl.
Compounds of the invention of formula (Ia) are those in which RI is in position 2 and R2is in position 5 of the phenyl.

Among the compounds that are the subject of the invention, mention may be made of compounds for which :
- Ri represents a group -O- (Cl_C $) alkyl and / or;
R2 represents a group (C1-C8) alkyl, (C3-C, p) cycloalkyl, perfluoro (C₁-C8), C4) alkyl or -O- (C1-C8) alkyl.
Among these compounds, there may be mentioned a subgroup of compounds for which:
- Ri represents a group -O- (Cl_C $) alkyl and / or;
R2 represents a group (C1-C8) alkyl, (C3-Clp) cycloalkyl or -O- (C1_ C8) alkyl.

Among the compounds that are the subject of the invention, mention may be made of a first group of compounds of general formula (1) or (Ia) in which R3 represents a group of formula - (CH2) to A where a represents 1, 2, 3 or 4, and A is selected in the group consisting of :
1 1 '1' ' NNN
_ ~ D; _ 3; -0; O and -0

7 where R7, R1, R2, Y and p are as previously defined.

Among the compounds that are the subject of the invention, there may be mentioned a second group of compounds of general formula (I) or (Ia) wherein R3 represents a group of formula -CO (CH2) bA where b is 0, 1, 2, 3 or 4, and A is selected in the group consisting of:

(~ ~ 7 17 NN \
and O
where R7, R1, R2, Y and p are as defined above.

Among the compounds object of the invention mentioned above in the first group and in the second group there may be mentioned a subgroup of compounds for which A is selected from the group consisting of:
O
and where R 1, R 2, Y and p are as previously defined.
Among the compounds that are the subject of the invention, there may be mentioned a third group of compounds of general formula (I) or (Ia) wherein R3 represents a group -B
wherein B is selected from the group consisting of:
IR R

NSN
-CN-R7; -O; -0; --CO; --0; and where R7, R1, R2, Y and p are as defined above.

Among the compounds object of the invention cited so far, mention may be made of first subgroup of compounds for which R7 is selected in the group consisting of = - (C 1 -C 8) alkyl-COO- (C 1 -C 6) alkyl, = -CO- (Cl-C $) alkyl where the alkyl is substituted by at least one atom halogen, = - (C3-C10) cycloalkyl, = phenyl,

8 = -SO 2 - (Cl-C $) alkyl where the alkyl is substituted by at least one atom halogen, = S-phenyl where the phenyl is substituted by at least one -O-C8) alkyl, = -SOZ-heteroaryl where the heteroaryl is a pyrazole or an isoxazole or a imidazole and where the heteroaryl is independently substituted by at least one group selected from halogen or - (C 1 -C 8) alkyl, = -SO2-N ((C1-C8) alkyl) 2, = -SO2-OH, = -CO-NH ((C 1 -C 8) alkyl), = - (C 1 -C 8) alkyl-CN, = - (C 1 -C 8) alkyl-COOH, = - (Cl-C8) alkyl-COO-M
= - (C1-C8) alkyl-OH, = - (C, -C8) alkyl-tetrazole, = - (Cl-C8) alkyl-CO-NH2i where M + is an alkali metal cation selected from Li +, Na + and K +, and when there are two substituents alkyl or cycloalkyl bonded to the nitrogen atom, they can be independently identical or different. As well as a second subgroup of compounds for which R7 represents -SOZ- (C3-Clo) cycloalkyl.

Among the compounds of formula (I) of the invention mentioned so far, it is possible especially cite the following compounds:
4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-Cyclopropyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- (1- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (1-Isopropylcarbamoyl-piperidin-3-yl) -piperazine-1-carboxylic acid, 4- (1- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (1-Cyclopropanesulfonyl-piperidin-4-yl) -piperazine-l-carboxylic acid, 3 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl)) - ethyl ester thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -propionic acid, 3 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -propionic acid, 4 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl)) ethyl ester thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -butyric acid, 4 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyl] -piperazin-l-ylmethyl} -piperidin-1-yl) -butyric acid,

9 5 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl)) - ethyl ester thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperid-1-yl) -pentanic acid, 5 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) pentanoic acid, [4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4-cyclohexyl-piperazine-1-carboxylic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-yl) -piperazin-1-carboxylic acid.
More particularly, mention may be made of the following compound: [4- (5-cyclohexyl-2-10 (meth) -phenyl) -thiazol-2-yl] -amide of 4- (Tetrahydropyran-4-yl) -piperazine 1-carboxylic acid.

Among the compounds of formula (I) of the invention mentioned so far, it is possible again include the following compounds:
[4- (5-Cyclohmethyl-2-methoxy-phenyl) -thiazol-2-yl] -am ide of 4 - ((S) -Cyclopropyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-carbonyl) -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-Carbamoylmethyl-piperidin-3-ylmethyl) -piperazine-l-carboxylic acid, ((S) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -acetic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -5-fluoro-thiazol-2-yl] -amide acid ((S) -1-Cyclopropyl-piperidin-3-ylmethyl) -piperazine-l-carboxylic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-ylmethyl) -piperazine-1-carboxylic acid, ((S) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl)) - ethyl ester thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -acetic acid, [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -am ide of 4 - [(R) -1- (2-cyano-ethyl) -piperidin-3-ylmethyl] -piperazine-1-carboxylic acid, sodium salt of 3 - ((R) -3- {4- [4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -propionic acid, [4- (5-Cyclohmethyl-2-methoxyphenyl) -thiazol-2-yl] -am ide of 4 - [(R) -1- (2-Carbamoyl-ethyl) -piperidin-3-ylmethyl] -piperazine-l-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((R) -1-Cyclopyropyridin-3-carboxyl-piperazine e-1-carboxyl ic, 4- (5-Butyl-2-ethoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-cyclopropyl-piperidin-3-ylmethyl) -piperazine-l-carboxylic acid, 4- (5-Cyclopentyl-2-ethoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-Cyclopropyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- (5-Butyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-cyclopropyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-Cyanomethyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4 - ((R) -1- [4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide Cyclopropyl-piperidin-3-yl) -piperazine-1-carboxylic acid, 4- (1- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (1-cyclopropyl-piperidin-4-yl) -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-

Cyclopropanesulfonyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-phenyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 2- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyl] -piperazinic acid;

ylmethyl} -piperidine-1-sulfonic acid, 4 - [(S) -1- (4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide Hydroxy-ethyl) -piperidin-3-ylmethyl] -piperazine-1-carboxylic acid, [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - [(S) -1-(2,2,2 Trifluoro-acetyl) -piperidin-3-ylmethyl] -piperazine-1-carboxylic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -5-fluoro-thiazol-2-yl] -amide acid (Tetrahydro-pyran-4-yl) -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-Dimethylsulfamoylpiperidin-3-ylmethyl) piperazine-1-carboxylic acid, [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - [(S) -1- (2H-) Tetrazol-5-ylmethyl) -piperidin-3-ylmethyl] -piperazine-1-carboxylic acid, 4- [1- (5- (4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;
Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl) -piperidin-2-ylmethyl] -piperazine-1 carboxylic acid, 4- [1- (1-C) 4- [4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;
dimethyl 1H-pyrazole-4-sulfonyl) -piperidi-2-ylmethyl] -piperazine-1-carboxylic acid, 4- [4- (5-Cyclohmethyl-2-methoxy-phenyl) -thiazol-2-yl] -am ide of 4- [1-(1,5-Dimethyl-1H-pyrazole-4-sulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- [1- (1- (4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide Methyl-1H
pyrazole-4-sulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- [1- (5- (4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;
methyl isoxazole-4-sulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- [4- (5-Cyclohmethyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- [1-(1-Methyl-LH
imidazole-4-sulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- (1- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (1-Dimethylsulfamoyl-piperidin-2-ylmethyl) -piperazine-1-carboxylic acid, 4- [1- (2,2,2-HCl) 4- [4- (5-cyclohexyl-2-methoxy-phenyl) thiazol-2-yl] -amide;
Trifluoro-ethanesulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- [1- (5-Cyclohexyl-2-methoxyphenyl) -thiazol-2-yl] -amide of 4- [1- (4-methoxy benzenesulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid,

11 4- [4- (5-Cyclopentyl-2-ethoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-yl) -piperazine-1-carboxylic acid, 4- [1- (3,5-bis (4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;
dimethyl isoxazole-4-sulfonyl) -piperid-2-yl methyl] -piperazine-1-carboxylic acid, 4- (5-Butyl-2-ethoxy-phenyl) -thiazol-2-yl] -amide of 4- (Tetrahydro-) pyran-4-yl) -piperazine-1-carboxylic acid, 4 - [(S) -1- (4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide methyl 1H-Imidazole-4-sulfonyl) -piperidin-3-ylmethyl] -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-ethoxy-phenyl) -thiazol-2-yl] -amide of 4- (Tetrahydro-) pyran 4-yl) -piperazine-1 = carboxylic acid, 4- [4- (5-Cyclopentyl-2-methoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-yl) -piperazine-1-carboxylic acid, 4- (5-Butyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (Tetrahydro-) pyran-4-yl) -piperazine-1-carboxylic acid, 4- [2- (2-Methoxy-5-pyropoxypenyl) -thiazol-2-yl] -amid of 4- Acid (Tetrahydro-pyran 4-yl) -piperazin-1-carboxylic acid, 4- (5-propyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (Tetrahydro-) pyran 4-yl) -piperazine-1-carboxylic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-yl) - [1,4] diazepane-1-carboxylic.

Among the compounds that are the subject of the invention, there may be mentioned a fourth group of compounds of general formula (I) or (La) in which R3 represents a group of formula - (CHAI-C where a represents 1, 2, 3 or 4, and C is selected in the group consisting of :

Rb Rc Rb 1 8 Rc Rf Rg Rf 0 \ 0 Rg R s Ra ~ Rd Ra Rd Rd Re Rh Re Rh and where R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R2, Y and p are such that defined previously.

Among the compounds that are the subject of the invention, there may be mentioned a fifth group of compounds of general formula (I) or (La) in which R3 represents a group of formula -CO (CH2) bC where b is 0, 1, 2, 3 or 4, and C is selected in the group consisting of:

Rb Rc Rb i 8 Rc Rf Rg Rf 0 \ o Rg R s Ra Rd Ra N Rd Re S Rh Re S Rh ,,, and

12 where R8, R9iRa, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R2, Y and p are as defined previously.

Among the compounds object of the invention mentioned above in the fourth group and in the fifth group we can cite a first subgroup of compounds for which C is selected from the group consisting of:
Rb o R Rd Re Rf S Rg Rf 0 \ / 0 Rg R a Ra Rh Re Rh and where R9, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R2, Y and p are as defined previously.
1o Among the compounds object of the invention mentioned above in the fourth group and in the fifth group, we can cite a second subgroup of compounds for which C represents:
R
Rb 18 Rc Ra N Rd where R8, Ra, Rb, Rc, Rd, R1, R2, Y and p are as defined above.
Among the compounds that are the subject of the invention, there may be mentioned a sixth group of compounds of general formula (I) or (Ia) wherein R3 represents a group -D
wherein D is selected from the group consisting of:
Rb Rc Rb 8 Rc Rf Rg Rf 00 Rg R
Ra ~ Rd Ra Rd Rd Re Rh Re Rh and where R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R2, Y and p are such that defined previously. Among this sixth group, we can cite a subgroup of compounds for which R8 is a hydrogen atom or a (C1-C8) alkyl group alkyl.

Among the compounds of formula (I) of the invention mentioned in the third, fourth, fifth group and their subgroups may include compounds following:
[4- (5-Cyclohexyl-2-methoxy-p-henyl) -thiazol-2-yl] -am ide of 4- (1,1-dioxo hexahydro-1-16-thiopyran-4-yl) -piperazine-1-carboxylic acid,

13 4- (4-Hydroxy) 4- [4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;

cyclohexyl) -piperazine-1-carboxylic acid, 4- (1,2,2,6,6-) 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;

Pentamethyl-piperidin-4-yl) -piperazine-1-carboxylic acid, 4- (2-Cyclohexyl-2-methoxy-phenyl) thiazol-2-yl] -amide of Tetramethyl-piperidin-4-yl) -piperazine-1-carboxylic acid, 4- (2- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (2,2-Dimethyl tetrahydro-pyran-4-ylmethyl) -piperazine-1-carboxylic acid, 4- [4- (5-Cyclohmethyl-2-methoxy-phenyl) -thiazol-2-yl] -amid of 4- Acid (tetrahydro-thiopyran-4-yl) -piperazine-1-carboxylic acid.

Certain intermediates useful for the preparation of the compounds of formula (I) can also be used as the final product of formula (I), as well as will appear in the examples given below.
Similarly, certain compounds of formula (I) of the invention may serve in as Intermediates Useful for the Preparation of Compounds of Formula (I) according to the invention.

In the following, protective group Gp is understood to mean a group that allows, a protect a reactive function such as a hydroxyl or an amine while synthesis and, on the other hand, to regenerate the intact reactive function in end of synthesis. Examples of protective groups as well as methods of protection and deprotection are given in Protective Groups in Organic Synthesis, Green et al., 2nd Edition (John Wiley & Sons, Inc., New York).
By leaving group X is meant in the following, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with starting of a pair electronic. This group can thus be easily replaced by another group during a substitution reaction, for example. Such starting groups are, by for example, halogens or an activated hydroxyl group such as a mesyl (methanesulphonyl), tosyl (toluenesulfonyl), triflate, acetate, etc. of the examples of departing groups as well as references for their preparation are given in Advances in Organic Chemistry, J. March, 3rd Edition, Wiley Interscience, p.
310-316.
In what follows, the precursor of R1, R2 or R3 is understood to mean a substituent R'l, R'2 or R'3 can be converted into R1, R2 and R3 by ~ one or more reactions chemical.
Group Z in the following, a leaving group or a derivative functional carboxylic acid, such as an acid chloride, a mixed anhydride or symmetrical,

14 or the acid suitably activated for example with hexafluoro phosphate of benzotriazol-1-yloxytris (dimethylamino) phosphonium (BOP), O-benzotriazol-1 yl N, N, N'-N'-tetramethyluronium hexafluorophosphate (HBTU) or O-benzotriazol-N-N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU).
When one or more substituents R'1, R'2 and / or R'3 represent a group containing an amine or hydroxyl function, these functions can be protected intermediately: an amine function can be protected by a group alkanoyl, benzyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl, or 9-fluorenylmethoxycarbonyl (Fmoc), for example; a hydroxyl function can to be protected in the form of ether or ester, for example.

The compounds of the invention can be prepared according to different methods described in this patent application. In another aspect, the present The invention relates to processes for the preparation of the products of formula (I) and their intermediate products.
The compounds of formula (I) of the invention may be prepared according to diagram General 1 below.
Diagram 1 YY
S
I 1) coupling agent R ~ N ~ H ~ N ~ (CHZ) P
~ N "NHa ~ JL
Ri t ~ N \
e R 2) R2 Ra 2 2 (II) NH N-R 3 '(I) \ 42) P

(Ili) According to Scheme 1, the compounds of the invention are obtained by coupling the aminothiazole derivative of formula (II) wherein R1, R2, Y are such that defined in the foregoing, with an amine derivative of formula (III) in which R'3 represents a precursor group of R3 or a group R3 as defined in this who precedes and p is as defined in the foregoing.
The aminothiazole derivatives of formula (II) can be obtained according to methods described in the patent application WO2004 / 096798.
According to Scheme 1, the aminothiazole derivative of formula (II) is brought into the presence a coupling agent for a period of 2 to 16 hours, then with the derivative amine of formula (III) for a period of 0.5 to 4 hours.

The coupling agent may be chosen from those known to those skilled in the art, by phosgene, di- (N-succinimidyl) carbonate, 1,1'-carbonyl-diimidazole, according to the methods described in Encyclopedia of Reagents for Organic Synthesis, LA Paquette, Volume 2, p 1006; volume 4, p 2304; volume 6, p 4107.
The reaction can be carried out in different solvents, for example dichloromethane, dimethylformamide, toluene, in the presence of a base such that triethylamine, K2CO3, at a temperature ranging from 0 C to 100 C.

The amino derivatives of formula (III) are known or can be prepared according to the 10 methods described in particular in the document WO 87/01706 or according to methods described in the following.
In what follows, the groups A 'and C' respectively represent a group precursor of group A or C, or a group A or C as defined previously.
The compounds of formula (III) in which R'3 represents a group precursor of

R3 or a group R3 as defined above and wherein p is such that defined in the foregoing, are obtained from compounds of formula (IV) by deprotection of nitrogen from piperazine or protected homo-piperazine according to methods known to those skilled in the art or described in the literature (W003 / 104230 and W003 / 057145).
For example, we can proceed as follows:
Gp H
BOY WUT
N ~
C ~ (CH2) PN \ (CH2) P
N NO
I
R'3 R'3 (IV) (III) The compounds of formula (IV) are commercially available or can be synthesized at from commercial compounds, according to methods known to the human job.
Compounds of formula (IV), wherein R'3 represents a group precursor of the group R3 with R3 representing a group -CO (CH2) bA or -CO (CH2) bC
(compounds of formula (IV.2) or (IV.5)) can also be obtained according to the following diagram 2:
Figure 2

16 Gp.N ((CHa) p O Gp, N - CH 2) p ~, Nf H + Z% _ (CHz) bA '- ~ N_ ~ - (CH2) bA' (IV.2) (R3 = -CO (CHa) b A ') (V.1) O
Gp.N__CHZ) p 0 Gp = N - CHZ) p ~, NH + Z% 1_ (CHz) bC '~, Nr- (CH2) eC' (IV.5) (R3 = -CO (CH2) b C ') O
(V.2) According to scheme 2, a mono-protected piperazine or homo-piperazine (Gp =
BOC or Gp = Benzyl) reacts with a compound of formula (V.1) or (V.2) in which Z represents a leaving group, or a group resulting from the activation of a carboxylic acid function, to give respectively the compound of formula (IV.2) or (IV.5) by acylation or peptide coupling in the presence a such as K2CO3, triethylamine, diisopropylethylamine or carbonate of optionally in the presence of a coupling reagent such as BOP, TBTU or CDI, in a solvent such as THF, acetonitrile or DMF at temperatures ranging from 0 C to 150 C.

Compounds of formula (IV), wherein R'3 represents a group precursor of the group R3 with R3 representing a group - (CH2) to A or - (CH2) aC (compounds of formula (IV.1) or (IV.4)), can also be obtained according to scheme 3 next :
Figure 3 Gp, Ni (CH ~H-Gp, N ~~ CHz) p ## STR5 ##
(VL1) Gp.N ((CH 2) P ~H-Gp-N ~ (CH 2) p ~ Nf H + H (CH2) ~. lC '-> ~ NI (IV.4) (R3' - - (CH2) to C ') (VI.2) ~ (CHz) a-C ' According to this method, a mono-protected piperazine or homo-piperazine (Gp =
BOC or Gp = Benzyl) reacts with an aldehyde of formula (VI.1) or (VI.2) for give respectively the compound of formula (IV.1) or (IV.4) in the terms of a reductive amination reaction in the presence of a reducing agent such as NaHB (OAc) 3, NaBH3CN in a solvent such as 1,2-dichloroethane, dichloromethane, methanol, THF at temperatures ranging from 0 C to 70 C
(Commun Synth, 1998, 28 (10), 1897-1905, J. Org Chem., 1992, 57 (11), 3218-3225, J. Org. Chem, 1996, 61, 3849-3862, Tetrahedron Lett., 1990, 31, 5595-5598).
Alternatively, the compounds of formula (IV.1) and (IV.4) can be synthesized by a substitution reaction according to the process illustrated in Scheme 4 next :

17 Figure 4 Gp, N- ~, ~ CH2) p ~ Gp, N ~ (CHZ) P
~ NH + X- (CH2) aA ~ NI ~ ~ (IV.1) (R3 '_ - (CH ~) to A ~) (VI1.1) (CHZa-A
Gp.Ni (CH2) p Gp'N --_ ~ CH2) p X- (CH) to C 'N
~ NH + (VIIz.2) - (CHz) a-Cl (IV.4) (R3 '= - (CH2) to C') According to scheme 4, a mono-protected piperazine or homo-piperazine (Gp =
BOC or Gp = Benzyl) reacts with a compound of formula (VI I.1) or (VI I.2) in which X represents a leaving group to give respectively the compound of formula (IV.1) or (IV.4). The reaction is carried out without a solvent or in a solvent such tetrahydrofuran, dimethylformamide, toluene, or acetonitrile in lack of base or in the presence of a base such as triethylamine or K2C03, to temperatures ranging from room temperature to 200 C for a period from 1 to 24 hours.
Compounds of formula (IV), wherein R'3 represents a group precursor of the group R3 with R3 representing a group -B or -D (compounds of formula (IV.3) or (IV.6)), can be prepared by reaction of a piperazine or a mono-protected homo-piperazine (Gp = BOC or Gp = Benzyl) and a B 'ketone precursor of B or of a precursor ketone of D, by reaction amination reducing agent in the presence of a reducing agent such as NaHB (OAc) 3, NaBH3CN in a solvent such as 1,2-dichloroethane, methanol, dichloromethane, THF to temperatures ranging from 0 C to 70 C according to the scheme below:
Figure 5 Gp.N ~ (CH2) p B ~ Gp, N-- ~ 4CH2) p ~ Nf H H- ~ N \ B ~ (IV.3) (R3 '= D') Gp.N__CH2) p D1 Gp, N - (CH2) p ~ NHH ~ NI, D1 (IV.6) (Rs = BI) The ketones B 'and D' used are commercial or can be synthesized according to the methods described in Organic Process Research & Development, 2004, 8, 939; Synthesis, 1989, 10, 767 The compounds of formula (I) may also be prepared according to scheme 6 below.
after.
Figure 6

18 YS
S 1) Agent of O
NNH coupling I ~ NNCHz) P Gp R z R1 H ~ 1 NOT
R2 2) HN --- f CHz) P R2 \ GP
(II) ~ 1N \ Gp (VIII) ZJL- (CHz) b -A '(V.1) O
or = Z ~ 1_ (CHz) bC '(V.2) O
(CHz) a.1-A NI.1) CH) P
O
eR2 N ~ NCHZ) P ~ u = HO N
~ SH or = H ~ (CH). - '1.2 H ~~ NN' z R2 za ~ C (U) R3 (Ix) or = x- (CHz) ~ A '(Vn.1) (I) or = X- (CHz) to C '(VII.2) or = B.
or = U

According to scheme 6, the aminothiazole derivative of formula (II) as defined in what precursor is coupled to a mono-protected piperazine or homo-piperazine (Gp =
BOC or Gp = Benzyl) to give the compound of formula (VIII).
The reaction is carried out under the same conditions as those described above.
above for diagram 1.
The compound of formula (VIII) is then deprotected to yield the compound of formula (IX), according to the methods known to those skilled in the art, which is react with a compound of formula (V.1), (V.2), (VI.1), (VI.2), (VII.1) or (VII.2), or with a ketone of formula B 'or of formula D' as defined above.
This The reaction is carried out according to the methods described above for syntheses intermediates of formula (IV).

In the general synthetic schemes, the starting compounds and the reagents, when their method of preparation is not described, are available in the trade or described in the literature, or may be prepared according to of the methods described therein or which are known to those skilled in the art.

The following examples describe the preparation of compounds according to the invention. The numbers of the exemplified compounds refer to those given in Table I, which illustrates the chemical structures of some compounds according to the invention.

19 In the following preparations and examples:
- CyHex = a cyclohexyl group;
- DSC = di- (N-succinimidyl) carbonate - CDI = 1,1'-carbonyl-diimidazole - DCE = dichloroethane - TBME = tert-butyl-methyl-ether - TA = ambient temperature, DCM = dichloromethane, DIPEA = diisopropylethylamine, THF = tetrahydrofuran, BOP = benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate, DMF = dimethylformamide, Boc = tertbutyloxycarbonyl, - TFA = trifluoroacetic acid (trifluoroacetic acid, in French), TBTU = 2- (1H-Benzotriazol-1-yl) -1,1,3,3-tétraméthyluroniumtétrafluoroborate, - HOBT = hydroxybenzotriazole, BSA = bis (trimethylsilyl) acetamide, AcOEt = ethyl acetate, - AcCl = acetyl chloride.
- PF = Fusion Point (in degrees Celsius) as measured on a Büchi device B545 with a temperature gradient of 1 C per minute.
- MH + = molecular mass of the form of the molecule ionized by a proton.
The compounds are analyzed by coupling HPLC - UV - MS (chromatography liquid - UV detection - mass spectrometry). The device used, marketed by Agilent, is composed of an HP1100 chromatograph equipped with a detector Agilent diode array and MSD quadrupole mass spectrometer Quad.
The analytical conditions are as follows:
Column: Symmetry C18 (50 x 2.1 mm, 3.5 μm) Eluent A: H20 + TFA 0.005% at pH 3.15 Eluent B: CH3CN + TFA 0.005%
gradient:
Time (min)% B

20 0 Column temperature: 30 C
Flow rate: 0.4 mL / min 5 Detection: a = 220 nm The compounds for which method B is indicated in Table I are analyzed by LCMS under the following conditions: YMC Jsphere column (33 x 2.1 mm, 4pm, eluent: CH3CN + 0.05% TFA: H20 + 0.05% TFA, gradient: 5:95 (0) min), then 95: 5 (2.5 min), then 95: 5 (3 min), flow rate: 1.3 mL / min, temperature: 30 C.
lo - tr = retention time.
NMR = nuclear magnetic resonance performed with a Bruker spectrometer Advance 200 (200 MHz). The solvent used is deuterated DMSO and Chemical shifts are expressed relative to the TMS. Abbreviations used are:
15 - s = singlet, - d = doublet, - dd = double doublet, - t = triplet, - m = multiplet, 20 - sel = expanded singlet.
The analysis of the optical purity is measured by Chiralpak AD HPLC column.
(250 mm x 4.6) eluted with a CO 2 / MeOH mixture 80/20 at 30 C with a flow rate of 3 mL / min at P = 20 MPa. The compounds are detected at 220 nm.
- aD = rotatory power. The rotational powers were determined with a Perkin-Elmer 241-MC polarimeter for the sodium D line (X = 589 nm), the concentrations are expressed as 10 mg / mL, measurements are made at ambient temperature.

EXAMPLE 1 = B4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide of Acid 4 - ((S) -1-Cyclopropyl-piperidin-3-ylmethyl) -piperazine-l-carboxylic acid (Compound N 1) 1.1. Preparation of the tert-butyl ester of the acid (R) -3-((Methylsulfonyloxy) methyl) piperidine-1-carboxylic acid To a solution of 5 g of the tert-butyl ester of the acid (R) -3-(hydroxymethyl) piperidine-1-carboxylic acid in 80 mL of DCM cooled to 0 C, 2.16 ml of methanesulfonyl chloride and then 3.86 ml of triethylamine are added.
The

21 medium is stirred for 1 hour at 0 ° C., then 0.7 ml of triethylamine is added and 0.54 mL
of methanesulfonyl chloride. After 30 min at 0 ° C., the medium is hydrolysed, the organic phase is washed twice in water and then with saturated solution of NaCl then dried over MgSO4. The medium is evaporated to give 6.8 g of oil pale yellow.
1.2. Preparation of the tert-butyl ester of the acid (S) -3 - ((4-benzylpiperazin-1-yl) methyl) piperidine-1-carboxylic acid The crude product obtained in stage 1.1 is dissolved in 75 ml of toluene. We 12.16 g of benzylpiperazine are added, the reaction medium is sealed and then heated for 5 hours at 150 ° C. After returning to RT, the medium is diluted in a mixed ether / pentane (1/1), washed twice with saturated NaHCO3 solution, two times in water and then with saturated NaCl solution. After drying on MgSO4 and evaporation, the crude is purified by flash-chromatography on silica gel for give 5.73 g of the expected solid.
MH + = 374.3 at t = 5.26 min 1.3. Preparation of the tert-butyl ester of the acid (S) -3- (piperazin-1-ylmethyl) piperidine-1-carboxylic acid A solution of 4.0 g of the compound obtained in step 1.2 in 30 mL of methanol is hydrogenated in a closed reactor, under irradiation with microwaves, at 80.degree.
VS
for 10 minutes in the presence of 1.7 g of 10% wet Pd / C and 2.02 g of ammonium formate. The medium is filtered and evaporated to give 2.89 g of colorless oil.
1.4 Preparation of the tert-butyl ester of (S) -3 - ((4- (4- (5-cyclohexyl-2-methoxyphenyl) thiazol-2-ylcarbamoyl) gipérazin-1-yl) methyl) -1- pigéridine carboxylic To a solution of 2.78 g of 4- (5-cyclohexyl-2-methoxyphenyl) thiazol-2-amine, compound described in patent application WO2004 / 096798, in 7 mL of dichloromethane, 2.59 g of DSC are added and the medium is stirred for 12 hours.
hours at TA. 2.59 g of the compound described in step 1.3 are added and the medium is agitated for 3 hours at RT. The medium is hydrolysed with a solution of NaHCO3 saturated then extracted in the DCM. The organic phase is washed with water and then with a saturated solution of NaCl. After drying over MgSO4, the solution is concentrated and purified by flash chromatography on silica gel to give 4.0 g of compound expected in the form of a white solid.
MH + = 598.7 at t = 8.26 min

22 1.5 Preparation of 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide acid 4- (R) -1-Piperidin-3-ylmethyl) -piperazine-1-carbox league To a solution of 4 g of compound obtained in step 1.4 in 10 ml of dioxane, 42 ml of a 4M solution of HCI in dioxane. The medium is stirred for 4 hours at RT. The environment is filtered, the solid is rinsed with ether and then taken up in the DCM and treated with soda 1 M. The The organic phase is washed with water and then with a saturated solution of NaCl.
After drying over MgSO 4, the solution is concentrated to give 3.16 g of the compound wish.
MH + = 498.7 at t = 6.27 min 1.6 Preparation of 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide acid 4 - ((S) -1-Cyclopropyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid To a solution of 0.2 g of the compound described in step 1.5 in 5 mL of MeOH, add 0.35 g of (1-ethoxycyclopropoxy) trimethylsilane and then 0.05 g of NaBH3CN
and 0.24 g of acetic acid. The medium is stirred for 2 hours at 60 ° C. The medium is concentrated then taken in AcOEt. The organic phase is washed twice with a solution of NaHCO3 saturated then with a saturated solution of NaCl. After drying on MgSO4, the organic phase is concentrated and then purified by flash-chromatography to give 0.16 g of the expected product.
PF = 88 C
ao = + 4 (c = 1, MeOH) Example 2: [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide) acid 4- (1-isopropylcarbamoyl-piperidin-3-yl) -piperazine-1-carboxylic acid (Compound N 2) 2.1. Preparation of tert-butyl ester of 4- (1-benzylpiperidin-3-) yl) piperazine-1-carboxylic acid To a suspension of 9.96 g of the monohydrochloride hydrate of the 1-benzylpiperidin-3-one in suspension in 200 mL of DCM, 20 mL of a 10% soda solution. The medium is agitated, the organic phase is decanted then washed with saturated NaCl solution. After drying on MgSO4, the phase organic is concentrated. The gum obtained is taken up in 180 mL of DCE, 10.1 g of Boc-piperazine then 15.9 g of NaBH (OAc) 3 and the medium is added.
restless 12 h to TA. The medium is concentrated and then taken up in AcOEt. The organic phase is washed twice with saturated NaHCO3 solution and then with a solution saturated with NaCl. After drying over MgSO4, the organic phase is concentrated

23 to give 18.63 g of the expected product.
PF = 103 C
2.2. Preparation of 1- (1-benzyipiperidin-3-yl) piperazine To a solution of 9.2 g of the compound obtained in step 2.1 in 85 mL of DCM, add 30 g of TFA. The medium is stirred for 5 hours at RT and then concentrated. The gross got is taken up in DCM and then washed 4 times with a 2M sodium hydroxide solution. The sentence organic is washed with a saturated solution of NaCl. After drying on MgSO4, the organic phase is concentrated to give 6.32 g of the expected product.
1H NMR: S (ppm) = 7.28 (sel, 5H), 3.43 (sel, 2H), 2.88 (d, 1H), 2.70 (d, 1);
H), 2.64 (m, 4H), 2.43-2.22 (m, 5H), 1.85-1.58 (m, 4H), 1.39 (ddd, 1H), 1.15 (ddd, 1;
H).
2.3. Preparation of 4- (5-cyclohexyl-2-methoxyphenyl) -thiazol-2-yl-amide 4- (1-Benzyl-piperidin-3-yl) -piperazine-1-carboxylic acid The procedure is identical to that described in Example 1 from 4-(5-cyclohexyl-2-methoxyphenyl) thiazol-2-amine described in the patent application WO2004 / 096798 and the compound obtained in step 2.2.
PF = 90 ° C
2.4. Preparation of 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide 4-piperidin-3-yl-piperazine-1-carboxylic acid To a solution of 1.69 g of the compound obtained in step 2.3 in 10 mL of DCE, add at 0 C, 1.26 g of chloroethylchloroformate. The medium is brought back to TA
then refluxed for 45 minutes. The medium is evaporated and then taken up in 10 mL
of MeOH and heated for 1 h at reflux. The crude is filtered, the solid is rinsed in the ether then dried to give 1.27 g of the expected compound as a trihydrochloride.
PF = 240 C
MH + = 484.7 at 6.81 min 2.5. Preparation of 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide 4- (1-Isopropylcarbamoyl-piperidin-3-yl) -piperazine-1-carboxylic acid To a solution of 0.2 g of the compound obtained in step 2.4 in 1.2 mL of DCM, Add 0 C, 0.06 mL of isopropyl isocyanate. The medium is stirred for 2 hours at 0 ° C.
then hydrolyzed with 5 mL of water and diluted with 10 mL of DCM. The organic phase is washed twice with saturated NaHCO3 solution and then with a solution saturated with NaCl. After drying over MgSO4, the organic phase is concentrated then purified by flash chromatography to give 0.16 g of the expected product.
PF = 134 C
MH + = 568.7 at t = 7.61 min

24 Example 3: = 4-(5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-acid amide 441-Cyclopropanesulfonyl-piperidin-4-yl) -piperazine-1-carboxylic acid (Compound N 3) 3.1 Preparation of 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide acid 4- (1-benzyl-piperidin-4-yl) -piperazine-1-carboxylic acid The procedure is identical to that described in Example 1 from 4- (5-cyclohexyl-2-methoxyphenyl) thiazol-2-amine, described in the patent application WO2004 / 096798, and 1- (1-benzyl-piperidin-4-yl) -piperazine.
PF = 81 C
3.2. Preparation of 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide 4-piperidin-4-yl-piperazine-1-carboxylic acid To a solution of 1.77 g of the compound obtained in step 3.1 in 10 mL of DCE, Add to 0 C, 1.31 g of chloroethylchloroformate. The medium is brought back to TA
then refluxed for 45 minutes. The medium is evaporated and then taken up in 10 mL
of MeOH and heated for 1 h at reflux. The crude is filtered, the solid is rinsed in the ether then dried to give 1.27 g of the expected compound as a trihydrochloride.
MH + = 484.6 at 6.21 min 3.3. Preparation of 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide 4- (1-Cyclopropanesulfonyl-piperidin-4-yl) -piperazine-1-carboxylic acid To a solution of 0.2 g of the compound described in Preparation 3.2 in DCM, we adds 0.04 MI of cyclopropylsulfonyl chloride and then 0.06 mL of triethylamine. The medium is stirred at RT for 4 h. The medium is diluted in the DCM then hydrolysis with 5 mL of water. The organic phase is washed twice with a solution of NaHCO3 saturated then with a saturated solution of NaCl. After drying on MgSO4, the organic phase is concentrated and then purified by flash-chromatography to give 0.18 g of the expected product.
Mp = 138 ° C
MH + = 588.8 at t = 7.49 min Example 4: 3 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy) ethyl ester phenyl) -thiazol-2-ylcarbamoyll-piperazin-l-ylmethyl} -piperidin-1-yl) -propionic (Compound N 4) To a solution of 0.2 g of the compound described in step 1.5 in 2 mL of toluene, we add 0.08 mL of triethylamine then 0.05 mL of the ethyl ester of 3-bromo propionic acid. The medium is stirred for 48 hours at RT. The medium is diluted in ether ethyl then filtered. The filtrate is washed with water and then with a saturated solution of NaCl. After drying on MgSO4, the organic phase is concentrated to give 0.21 g of expected product.
MH + = 598.8 at t = 6.84 min Example 5: 3 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-acid ylcarbamoyll-piperazin-1-ylmethyl} -piperidin-1-yl) -propionic (Compound N 5) To a solution of 0.208 g of the compound described in step 4 in 3 mL of methanol, we 0.31 mL of 5M sodium hydroxide is added at 0 ° C. The medium is stirred for 24 hours at RT. The environment is concentrated then taken up in water. A solution is added drop by drop of HCI 6N
until the appearance of a precipitate. The solid is extracted in the DCM then after drying on MgSO4, the organic phase is concentrated to give 0.15 g of expected product.
15 MH + = 570.7 at t = 6.64 min PF = 144 C

Example 6: [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide of the acid 4- (Tetrahydro-pyran-4-yl) -piperazine-1-carboxylic acid (Compound No. 11) This compound can be obtained according to the process described in Preparation 1.4 enter 4- (5-cyclohexyl-2-methoxyphenyl) thiazol-2-amine and 1- (tetrahydro-2H);
pyran-4-yl) piperazine described in J. Med. Chem .; IN; 47; 11; 2004; 2833 - 2838.
Another method of synthesis is possible:
6.1 Preparation of the tert-butyl ester of 4-β- (5-cyclohexyl-2-methoxy

Phenyl) -thiazol-2-ylcarbamoyllpiperazine-1-carboxylic acid To a solution of 3.0 g of 4- (5-cyclohexyl-2-methoxyphenyl) thiazol-2-amine, compound described in patent application WO2004 / 096798, in 100 ml of dichloroethane, 2.9 g of DSC are added and the medium is stirred for 16 hours.
hours at TA. 2.0 g of BOC-piperazine are added and the medium is stirred for 3 hours.
hours to YOUR. The medium is hydrolysed with a solution of saturated NaHCO3 and then extracted in the DCM. The organic phase is washed with water and then with a saturated solution of NaCl.
After drying over MgSO 4, the solution is concentrated and purified by flash chromatography on silica gel to give 5.1 g of the expected compound under the shape of a beige solid.
MH + = 501.7 at t = 11.72 min

26 6.2 Preparation of (4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide piperazine-1-carboxylic acid To a solution of 5.1 g of the compound obtained in step 6.1 in 100 mL of dioxane, 19 ml of a 4M solution of HCl in dioxane are added dropwise.
The medium is stirred for 4 h at RT. The medium is filtered, the solid is rinsed with ether then dried to give 4.38 g of a white powder. The solid is taken up in the DCM and treaty with 1M sodium hydroxide. The organic phase is washed with water and then with a solution saturated with NaCl. After drying over MgSO4, the solution is concentrated to give 3.7 g of the desired compound.
1o MH + = 401.6 at t = 7.19 min 6.3 Preparation of 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide acid 4- (tetrahydro-pyran-4-yl) -piperazine-1-carboxylic acid To a solution of 1.4 g of the piperazine obtained in step 6.2 in 13 ml of dichloroethane, 0.4 g of dihydro-2H-pyran-4 (3H) -one and then 1.59 g of NaBH (OAc) 3 and the medium is stirred for 72 h at RT. The middle is concentrated then taken back in the DCM. The organic phase is washed twice with a solution of NaHCO3 saturated then with a saturated solution of NaCl. After drying on MgSO4, the organic phase is concentrated to give 1.7 g of the expected product.
The beige powder obtained is purified by flash chromatography gel silica to give 1.42 g of the expected compound as a white solid.
MH + = 484.7 at t = 7.42 min PF = 226 C

Example 7: 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-acid amide 4- (Tetrahydro-pyran-4-carbonyl) -piperazine-1-carboxylic acid (Compound No. 13) To a solution of 41 mg of tetrahydro-2H-pyran-4-carboxylic acid in 0.7 mL of DCM, 122 mg of TBTU, 26 mg of HOBt and 0.17 ml of DIPEA are added at RT. The medium is stirred at RT for 1 hour 15 minutes and then 100 mg of the compound is added described in step 6.2. The medium is stirred for 12 hours at RT. The middle is taken again in the DCM, washed three times with saturated Na2CO3 solution and then with a solution saturated with NaCl. After drying over MgSO 4 and evaporation, 0.21 g of crude reaction which is purified by flash chromatography on silica gel for give 0.08 g of the expected compound as a white solid.
MH + = 513.7 at t = 9.88 min PF = 276 C

27 Example 8: 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide of the acid 4- (Tetrahydro-pyran-4-yimethyl) -piperazi: ne-1-carboxylic acid (Compound No. 17) To a solution of 0.155 g of the piperazine obtained in step 6.2 in 1.5 mL
of dichloroethane, 0.044 g of tetrahydro-2H-pyran-4-carbaldehyde is added, followed by after stirring for 1 hour at RT, 0.114 g of NaBH (OAc) 3 and the medium is stirred 12 pm to YOUR. The medium is diluted in DCM. The organic phase is washed twice with a solution of saturated NaHCO3 and then with a saturated solution of NaCl. After drying on MgSO4, the organic phase is concentrated to give 0.16 g of gross.
The solid is purified by flash chromatography on silica gel to give 0.12 g of the expected compound in the form of a white solid.
MH + = 499.7 at t = 7.75 min PF = 114 C

Example 9: 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-acid amide 4 - ((S) -1-carbamoylmethyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid (Compound N 14) 9.1 Preparation of the Ethyl Ester of ((S) -3- {4- (4- (5-Cyclohexyl) -2-methoxy phenyl) -thiazol-2-ylcarbamoyll-piperazin-1-ylméthyll-piperidin-1-yl) -Acetate (Compound N 18) This compound is synthesized from the compound described in Preparation 1.5 and of ethyl 2-bromoacetate according to a process identical to that described in preparation 4.
9.2 Preparation of ((S) -3-f4-f4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyll-piperazin-1-ylmethyl) -piperidin-1-yl) -activity (Compound N 15) This compound is synthesized from the compound described in Preparation 9.1 according to a process identical to that described in Preparation 5.
9.3 Preparation of 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide acid 4 - ((S) -1-Carbamoylmethyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid To a solution of 0.1 g of the compound described in step 9.2 in 1 ml of DCM, add 0.1 g of TBTU, 0.02 g of HOBt then 0.08 mL of DIPEA. After 2 hours stirring at RT, a stream of ammonia is bubbled into the solution during 2 hours: The reaction medium is then filtered, the filtrate is washed with solution of NaHCO3 saturated then with a saturated solution of NaCl. After drying on MgSO4, the organic phase is concentrated to give 0.09 g of crude.
The crude is purified by flash chromatography on silica gel to give 0.052 g

28 of the expected compound in the form of a white solid.
MH + = 555.7 at t = 6.68 min PF = 134 C

Example 10: Acetyl 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide 4 - [(S) -1- (2H-tetrazol-5-ylmethyl) -piperidin-3-piperazine-1-ylméthyll carboxylic acid (Compound N 42) 10.1 Preparation of 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-a ide of 4 - ((S) -1-Cyanomethyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid 10 (Compound No. 26) To a solution of 0.45 g of the compound obtained in step 1.5 in 4 mL of acetone, we add 0.1 g of Na2CO3. The medium is cooled to 0 C and then 0.06 mL of 2-chloroacetonitrile are added and the medium is stirred until it returns to RT. We adds 0.012 mL of 2-chloroacetonitrile and 0.02 g of Na2CO3. The medium is agitated 2 hours to TA then concentrated. The crude is triturated in water and extracted in ether.
The sentence The organic material is washed twice with saturated NaHCO 3 solution and then with a saturated solution of NaCl. After drying over MgSO4, the organic phase is concentrated and then purified by flash chromatography on silica gel for give 0.34 g of the expected compound as a white solid.
MH + = 537.7 at t = 7.67 min PF = 106 C
10.2 Preparation of 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide 4-f (S) -1- (2H-tetrazol-5-ylmethyl) piperidin-3-ylmethyl-piperazine-1-acid carboxylic To a suspension of 0.34 g of the compound synthesized in step 10.1 in a mixed of 3 mL of water and 1 mL of isopropanol, 0.06 g of NaN 3 and 0.14 g of ZnBr 2.
The mixture is heated at 80 ° C. for 40 hours, then 0.03 g of NaN3 and 0.07 g of ZnBr2 and stirring is maintained at 80 ° C. for 12 hours.
The medium is filtered, the solid is rinsed with water and then with ether. The solid is purified by Preparative HPLC to give 56 mg of the expected compound.
MH + = 580.7 at t = 7.32 min Example 11: 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-acid amide 4 - ((S) -1-phenyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid (Compound N 30)

29 11.1 Preparation of (R) -1-Benzyl-4- (piperidin-3-ylmethyl) piperazine To a solution of 1.35 g of the compound obtained in step 1.2 in 5 ml of dioxane, we 20 mL of a 4M solution of HCI in dioxane is added. The medium is stirred for 2 hours at TA.
The medium is filtered, the solid is rinsed with ether and then taken up in the DCM and treated by 1M sodium hydroxide. The organic phase is washed with water and then with a solution saturated with NaCl. After drying over MgSO4, the solution is concentrated to give 1 g of crude.
MH + = 274.3 at t = 5.52 min 11.2 Preparation of (S) -1-benzyl-4 - ((1-phenylpiperidin-3 yl) methyl) piperazine In a tube are placed 0.26 g of phenyl trifluoromethanesulphonate, 0. 8 g of the amine prepared in step 11.1 in 5.6 mL of NMP. The tube is heated under pressure in a microwave oven for 30 minutes at 230 C. After returning to TA, the The medium is hydrolysed and then extracted into ether. The organic phase is washed the water then with a saturated solution of NaCl. After drying over MgSO4, the solution is concentrated to give 0.41 g of crude. The solid is purified by fiash-chromatography on silica gel to give 0.067 g of the expected compound.
MH + = 350.3 at t = 9.97 min 11.3 Preparation of (S) -1 - ((1-phenylpiperidin-3-yl) methyl) piperazine To a solution of 0.066 g of the compound obtained in step 11.2 in 9 mL of methanol, 0.05 g of Pd / C 10%, humidified to 50%, are added. The medium is agitated to YOUR
for 48 hours under 10 bar of hydrogen. After filtration on celite, filtrate is evaporated to give 0.037 g of the desired compound.
11.4 Preparation of 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl-amide 4 - ((S) -1-phenyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid The procedure is identical to that described in Example 1 from 4- (5-cyclohexyl-2-methoxyphenyl) thiazol-2-amine, described in the patent application WO2004 / 096798, and amine obtained in step 11.3.
MH + = 574.8 at t = 8.12 min c ~>, c ~~~~~~~~~~~~~~~~~~~~~
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~~~ U ~ _ OR ~~ _ OR
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EE ~ EE ~
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L 'L''' F-CV N CV NN

O ~
s' O
o \ / ip ~ ~ OO z O
zcn O zva .z M
2 ~
U =
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UU = UU = UU =
UU
O p O pU 0 O

~ NM d ~ ~
LO LO LC) LO LO

O i aD
~ p OC
Q ~ CN fl ~~~ + (0 Q ~ C ct (~
QO_ tNQ OC OCY = O06 p (L) > + U
X (B -C p = N ~ C -COX - ~ _ O d d d d O N N N
~ p ~ CC p N ~, V ~ QN t (S ~ a C
U Xp OO ~~ UNO ~~
~ i -t3 d. X ~ + ~ r Q p CX ir ~ O ~ -X dd) OUNO ~ ~ ct X
> N (O ~ L p CQ (ü (iQ ~ NCN tIf 7 Q
p>, S2 U p ~ L Lf) p ~~ U (LU O ~ NU
Q ~ ~ (6 O j, = OC>, _ - ~ N- ON O.
UO>,> p 0 ONE N- NN
LO d N (L6 ~ t. ~ = (B
Lo (Q da ~
C C C C CO C CC ~ C C
Lo (0 ~ M "Zr N
II 0 II c ~ II d II ~ II ~?
_ ~ 2 (0 2 (0 _ !.
cu ~ = cv ~ -ca = co ~ Co ID a) ID ID
EEEEE
wwwww NN CV N cY) _ _ = 2 =
C1 0 C1 0 ~
ih NN
N = N
UU OR U ~

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~ ~ ~ ~ ~
ti ao rn o ~
LO ui m The compounds according to the invention have been the subject of pharmacological tests allowing to determine their modulatory effect of receptor activity at chemokines.
Chemokines are low molecular weight proteins that belong to the family of proinflammatory cytokines and are involved in the chemotaxis Leukocytes and endothelial cells. Chemokines control many biological processes and are associated with disorders inflammatory Appearing during stress, injury or infection the modulating the effects of chemokines can prevent or treat diseases such as asthma, arthritis, allergies, autoimmune immune, Atherosclerosis or angiogenesis (CD Paavola et al., J. Biol Chem.
1998, 273, (50), 33157-33165).
Among the chemokines, there is the hMCP-1 (of the English human Monocyte Chemotactic Protein) which belongs to the group of CC chemokines and which is a natural agonist of the CCR2b receptor.
The inhibitory activity of the compounds according to the invention was measured on cell expressing the human CCR2b receptor. The concentration of natural agonist hMCP-which inhibits 50% (IC50) of CCR2b receptor activity is 0.57 nM. The compounds according to the invention have a C150 generally between 0.1 M and 0.1 nM, and preferably between 100 nM and 0.1 nM. -In Millipore GF / B filter plates (ref MAFBNOB10 or 50), contact for 1 h 30 at room temperature: 50 μl of compound at 3 × 10 -5 M in the buffer reaction or range of MCP-1 cold ((R & D System). Recombinant human MCP-1) (final concentration of compound: 10-5 M), as well as 50% of MCP-1 iodine ((1251] -MCP-Recombinant 9human Bolton + Hunter labelled (Amersham)) at 0.3 nM in water Distilled (final concentration of iodinated MCP-1: 0.1 nM), as well as 50 μl of CHO cells K1-CCR2B (obtained from Euroscreen Brussels, Belgium) at 6 x 106 cells / ml (final concentration in the reaction buffer: 3 x 105 cells / well). The filters have previously been saturated with 100 μL of PEI at 0.0125% final in PBS for 72 hours at 4 C and the PEI was removed by filtration. The contents of the wells are filtered and washed twice

With the reaction buffer, and the filters are allowed to dry overnight.
The next day, 20NL / scintillating well <e Optiphase Super Mix Wallac are distributed. The filters are impregnated for 1 to 2 hours and then counted with Trilux Iode 125.1 min.
Reaction buffer = PBS buffer, 50 nM Hepes, 1 mM CaCl 2, 5 mM MgCl 2 0.5%
BSA without fatty acid, adjusted to pH 7.4.
For example, compound # 9 exhibited an IC 50 of 4 nM, compound no.
at presented a 53 nM C150, the compound no. 22 exhibited a 4 nM C150, the Compound No. 40 showed an IC 50 of 82 nM, compound No. 41 showed a IC.sub.50 of 39 nM, Compound No. 33 showed a Cl.sub.50 of 20 nM, Compound No. 11 20 nM IC50, compound 23 showed an IC50 of 8 nM, the Compound 29 showed an IC 50 of 50 nM and compound no.
C150 of 73 nM.
The compounds according to the invention can therefore be used for the preparation of medicinal products, in particular drugs that antagonize the effect of chemokines.
Thus, according to another of its aspects, the subject of the present invention is medicaments which comprise a compound of formula (I), or a the latter to a pharmaceutically acceptable acid, or a hydrate or a solvate.
These drugs find their therapeutic use, especially in the prevention and treatment of various pathologies such as:
- Acute and chronic immuno-inflammatory diseases and syndromes as atherosclerosis, restenosis, chronic lung diseases, particular COPD (chronic obstructive pulmonary disease); the syndrome of respiratory distress ; bronchial hyperactivity; colitis; silicosis;
the fibrous pathologies, pulmonary fibrosis, cystic fibrosis; the viral or bacterial infections, AIDS, meningitis, malaria, leprosy, tuberculosis, herpes, cytomegalovirus infections; septic shock, sepsis, the endotoxic shock; rejection of transplants; bone pathologies such than osteoporosis, osteoarthritis; conjunctivitis; dermatitis atypical or contact; eczema; glomerulonephritis; pancreatitis; colitis ulcerative diseases, autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, lateral amyotrophic sclerosis, Crohn's disease, the lupus erythematosus, scleroderma, psoriasis; Parkinson's disease ;
the Alzheimer's disease ; diabetes ; cachexia; obesity;
- the treatment of pain, particularly neuropathic and inflammatory;
- allergic diseases such as allergic respiratory diseases, asthma rhinitis, pulmonary hypersensitivity, delayed hypersensitivity;
- diseases and disorders in which the angiogenic processes are involved as cancers (intratumoral angiogenesis), diseases retinal (age-related macular degeneration: AMD);
- cardiac pathologies: hemodynamic shock; cardiac ischemia;
the post-ischemic reinfusion attacks; myocardial infarction, thrombosis coronary heart disease, heart failure, angina pectoris.

According to another of its aspects, the present invention relates to compositions pharmaceutical compounds comprising, as an active ingredient, a compound according to the invention. These pharmaceutical compositions contain an effective dose at less a compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, as well as at least one excipient pharmaceutically acceptable.
Said excipients are chosen according to the pharmaceutical form and the mode desired administration, among the usual excipients which are known to the skilled person.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous vein, topical, local, intratracheal, intranasal, transdermal or rectal, the active ingredient of formula (I) above, or its salt, ifivat or hydrate, may be administered in unit dosage form, in admixture with excipients pharmaceutical products, animals and humans for the prophylaxis or the treatment of the disorders or diseases above.
Appropriate unitary forms of administration include forms by way such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, forms of administration sublingual, oral, intratracheal, intraocular, intranasal, by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous forms of rectal administration and implants. For application topically, the compounds according to the invention can be used in creams, gels, ointments or lotions.
By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg Orally, the dose of active ingredient administered per day can reach 0.1 to 1000 mg / kg, in one or more doses.
There may be special cases where higher or higher dosages weak are appropriate; such dosages are not outside the scope of the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the mode of administration, the weight and the response of said patient.
The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which includes administration to a patient of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates.

Claims (27)

1. Compound of formula (I) below:

in which :
R1 represents a hydrogen atom, a halogen atom, a (C1-C8) alkyl group, trifluoro (C1-C4) alkyl, -OH, -O- (C1-C8) alkyl, -O-trifluoro (C1-C8) alkyl, -O-(C1 C8) alkyl- (C3-C10) cycloalkyl, -O- (C3-C10) cycloalkyl, -O-CH2-CH = CH2, -S- (C1-C4) alkyl;
R2 represents a hydrogen atom, a halogen atom, a -OH group, C8) alkyl, trifluoro (C1-C4) alkyl, perfluoro (C1-C4) alkyl, (C3-C10) cycloalkyl, -O- (C1-C8) alkyl, -O- (C1-C8) alkyl- (C3-C10) cycloalkyl, -O- (C3-C10) cycloalkyl, -O-CH = CH2, - (C1-C8) alkyl- (C3-C8) cycloalkyl;
Y represents a hydrogen atom or a halogen;
p represents 2 or 3;
R3 represents:

a1) a group of formula - (CH2) aA
where a represents 1, 2, 3 or 4, and A is selected from the group consisting of by :
where R7 is selected from the group consisting of:
.cndot. - (C 1 -C 8) alkyl-COO- (C 1 -C 8) alkyl, .cndot.-CO- (C1-C8) alkyl where the alkyl is substituted by at least one atom halogen, .cndot. - (C3-C10) cycloalkyl, .cndot. phenyl, .cndot. -COO- (C3-C10) cycloalkyl, = -SO2- (C1-C8) alkyl where the alkyl is substituted by at least one atom halogen, = -SO2-phenyl where the phenyl is substituted by at least one group -O- (C1-C8) alkyl, = -SO2-heteroaryl where the heteroaryl is a pyrazole, an isoxazole or a imidazole and where the heteroaryl is independently substituted by at least one group selected from halogen or - (C1-C8) alkyl, = -SO2-N ((C1-C8) alkyl) 2, = -SO 2 -OH, = -SO2- (C3-C10) cycloalkyl, = -CO-NH ((C1-C8) alkyl), = - (C1-C8) alkyl-CN, = - (C1-C8) alkyl-imidazole, = - (C1-C8) alkyl-COOH, = - (C1-C8) alkyl-COOM +, = - (C1-C8) alkyl-OH, = - (C1-C8) alkyl-tetrazole, = - (C1-C8) alkyl-CO-NH2, = - (C1-C8) alkyl-CO-NH ((C1-C8) alkyl), = - (C1-C8) alkyl-CO-NH ((C3-C10) cycloalkyl), = - (C1-C8) alkyl-CO-N ((C1-C8) alkyl) ((C3-C10) cycloalkyl), = - (C1-C8) alkyl-CO-N ((C1-C8) alkyl) 2, = - (C1-C8) alkyl-CO-N ((C3-C10) cycloalkyl) 2, where M + is an alkali metal cation selected from Li +, Na + and K +, and when there are two substituents alkyl or cycloalkyl bonded to the nitrogen atom, they can be independently identical or different a2) a group of formula -CO (CH2) bA
where b is 0,1,2,3 or 4, and A is selected from the group consisting of by :
where R7 is as previously defined;

a3) a group -B
wherein B is selected from the group consisting of:

where R7 is as previously defined;
a4) a group of formula - (CH2) aC
where a represents 1, 2, 3 or 4, and C is selected from the group consisting of by:
or :
- R8 is selected from the group consisting of:
.cndot. a hydrogen atom, .cndot. a (C1-C8) alkyl group, .cndot. - (C1-C8) alkyl-COO- (C1-C8) alkyl, .cndot.-CO- (C1-C8) alkyl wherein the alkyl is optionally substituted by at least a halogen atom, .cndot. - (C3-C10) cycloalkyl, .cndot. phenyl, .cndot. -COO- (C3-C10) cycloalkyl, .cndot.-SO2- (C1-C8) alkyl wherein the alkyl is optionally substituted with minus one halogen atom, .cndot.-SO2-phenyl where the phenyl is optionally substituted by at least one -O- (C1-C8) alkyl group, .cndot.-SO2-heteroaryl where the heteroaryl is a pyrazole, an isoxazole or a imidazole and where the heteroaryl is optionally independently substituted by at least one group chosen from halogen or - (C1-C8) alkyl, .cndot. -SO2-N ((C1-C8) alkyl) 2, .cndot. -SO 2 OH, .cndot. -SO2- (C3-C10) cycloalkyl, .cndot. -CO-NH ((C1-C8) alkyl), .cndot. - (C1-C8) alkyl-CN, .cndot. - (C1-C8) alkyl-imidazole, .cndot. - (C1-C8) alkyl-COOH, .cndot. - (C1-C8) alkyl-COO-M +, .cndot. - (C1-C8) alkyl-OH, .cndot. - (C1-C8) alkyl-tetrazole, .cndot. - (C1-C8) alkyl-CO-NH 2, .cndot. - (C1-C8) alkyl-CO-NH ((C1-C8) alkyl), .cndot. - (C1-C8) alkyl-CO-NH ((C3-C10) cycloalkyl), .cndot. - (C1-C8) alkyl-CO-N ((C1-C8) alkyl) ((C3-C10) cycloalkyl), .cndot. - (C1-C8) alkyl-CO-N ((C1-C8) alkyl) 2, .cndot. - (C1-C8) alkyl-CO-N ((C3-C10) cycloalkyl) 2, where M + is an alkali metal cation selected from Li +, Na + and K +, and when there are two substituents alkyl or cycloalkyl bonded to the nitrogen atom, they can be independently identical or different;
R9 is selected from the group consisting of: hydroxyl, O- (C1-C8) alkyl, -O-trifluoro (C1-C8) alkyl, -O- (C1-C8) alkyl- (C3-C10) cycloalkyl, -O- (C3-C10) cycloalkyl, Ra, Rb, Rc and Rd are independently a hydrogen atom or a group methyl, since at least one of Ra, Rb, Rc and Rd is a group methyl;
- Re, Rf, Rg and Rh are independently a hydrogen atom or a group methyl;

a5) a group of formula -CO (CH2) bC
where b is 0, 1, 2, 3 or 4, and C is selected from the group consisting of by :
where R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are as defined previously, a6) a group -D
wherein D is selected from the group consisting of:
where R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are as defined previously, in the basic state or acid addition salt, as well as in the state of hydrates or solvates. 2. Compound according to claim 1, of formula (la):

where R1, R2, R3 and Y are as defined in claim 1. 3. Compound according to claim 2, of formula (la), characterized in that R1 is in position 2 and R2 is in position 5. 4. Compound according to any one of claims 1 to 3, characterized in that than R1 represents -O- (C1-C8) alkyl. 5. Compound according to any one of claims 1 to 4, characterized in that than R2 represents a (C1-C8) alkyl, (C3-C10) cycloalkyl, perfluoro (C1-C4) alkyl or -O- (C1-C8) alkyl. 6. Compound according to claim 5, characterized in that R2 represents a (C1-C8) alkyl, (C3-C10) cycloalkyl or -O- (C1-C8) alkyl. 7. A compound according to any one of claims 1 to 6, characterized in that than R3 represents a group of formula - (CH2) aA where a represents 1, 2, 3 or 4, and A is selected from the group consisting of:

where R7, R1, R2, Y and p are as defined in claim 1. 8. A compound according to any one of claims 1 to 6, characterized in that than R3 represents a group of formula -CO (CH2) bA where b represents 0, 1, 2, 3 or 4, and A is selected from the group consisting of:

where R7, R1, R2, Y and p are as defined in claim 1. 9. A compound of any one of claims 7 or 8, characterized in that A

is selected from the group consisting of:

where R1, R2, Y and p are as defined in claim 1. 10. Compound according to any one of claims 1 to 6, characterized in that that R3 represents a group -B in which B is selected from the group consisting of :

where R7, R1, R2, Y and p are as defined in claim 1. 11. A compound as claimed in any one of claims 1 to 10, characterized in that is selected from the group consisting of:
.cndot. - (C1-C8) alkyl-COO- (C1-C8) alkyl, .cndot. -CO- (C1-C8) alkyl wherein the alkyl is substituted by at least one atom halogen, .cndot. - (C3-C10) cycloalkyl, .cndot. phenyl, .cndot. -SO2- (C1-C8) alkyl wherein the alkyl is substituted by at least one atom halogen, .cndot. -SO2-phenyl where the phenyl is substituted by at least one -O- (C1-C8) alkyl, .cndot. -SO2-heteroaryl where the heteroaryl is a pyrazole or an isoxazole or a imidazole and where the heteroaryl is independently substituted by at least one group selected from halogen or - (C1-C8) alkyl, .cndot. -SO2-N ((C1-C8) alkyl) 2, .cndot. -SO 2 OH, .cndot. -CO-NH ((C1-C8) alkyl), .cndot. - (C1-C8) alkyl-CN, .cndot. - (C1-C8) alkyl-COOH, .cndot. - (C1-C8) alkyl-COO-M +, .cndot. - (C1-C8) alkyl-OH, .cndot. - (C1-C8) alkyl-tetrazole, .cndot. - (C1-C8) alkyl-CO-NH 2, where M + is an alkali metal cation selected from Li +, Na + and K +, and when there are two substituents alkyl or cycloalkyl bonded to the nitrogen atom, they can be independently identical or different. 12. A compound as claimed in any one of claims 1 to 10, characterized in that represents -SO2- (C3-C10) cycloalkyl. 13. Compounds according to any one of claims 1 to 12, chosen from:

4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-Cyclopropyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- (1- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (1-Isopropylcarbamoyl-piperidin-3-yl) -piperazine-1-carboxylic acid, 4- (1- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (1-Cyclopropanesulfonyl-piperidin-4-yl) -piperazine-1-carboxylic acid, 3 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl)) - ethyl ester thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -propionic acid, 3 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -propionic acid, 4 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl)) ethyl ester thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -butyric acid, 4 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -butyric acid, 5 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl)) - ethyl ester thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) pentanoic acid, 5 - ((R) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) pentanoic acid, [4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4-cyclohexyl-piperazine-1-carboxylic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-yl) -piperazine-1-carboxylic acid. 14. Compound characterized in that it is:
4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-yl) -piperazine-1-carboxylic acid. 15. Compounds according to any one of claims 1 to 12, chosen from:

4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-Cyclopropyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-carbonyl) -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-Carbamoylmethyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, ((S) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -acetic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -5-fluoro-thiazol-2-yl] -amide acid ((S) -1-Cyclopropyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-ylmethyl) -piperazine-1-carboxylic acid, ((S) -3- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl)) - ethyl ester thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -acetic acid, 4 - [(R) -1- (4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide cyano ethyl) -piperidin-3-ylmethyl] -piperazine-1-carboxylic acid, sodium salt of 3 - ((R) -3- {4- [4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyl] -piperazin-1-ylmethyl} -piperidin-1-yl) -propionic acid, 4 - [(R) -1- (4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide Carbamoyl-ethyl) -piperidin-3-ylmethyl] -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((R) -1-Cyclopropyl-piperidin-3-carbonyl) -piperazine-1-carboxylic acid, 4- (5-Butyl-2-ethoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-cyclopropyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- (5-Cyclopentyl-2-ethoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-Cyclopropyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- (5-Butyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-cyclopropyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-Cyanomethyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((R) -1-Cyclopropyl-piperidin-3-yl) -piperazine-1-carboxylic acid, 4- (1- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (1-cyclopropyl-piperidin-4-yl) -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-Cyclopropanesulfonyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-phenyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, 2- {4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-ylcarbamoyl] -piperazinic acid;

ylmethyl} -piperidine-1-sulfonic acid, 4 - [(S) -1- (4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide Hydroxy-ethyl) -piperidin-3-ylmethyl] -piperazine-1-carboxylic acid, [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - [(S) -1-(2,2,2 Trifluoro-acetyl) -piperidin-3-ylmethyl] -piperazine-1-carboxylic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -5-fluoro-thiazol-2-yl] -amide acid (Tetrahydro-pyran-4-yl) -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - ((S) -1-Dimethylsulfamoyl-piperidin-3-ylmethyl) -piperazine-1-carboxylic acid, [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - [(S) -1- (2H-) Tetrazol-5-ylmethyl) -piperidin-3-ylmethyl] -piperazine-1-carboxylic acid, 4- [1- (5- (4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;
Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- [1- (1-C) 4- [4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;
dimethyl 1H-pyrazole-4-sulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- [1- (1,5-C) 4- [1- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;
dimethyl 1H-pyrazole-4-sulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- [1- (1- (4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide Methyl-1H
pyrazole-4-sulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- [1- (5- (4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;
methyl isoxazole-4-sulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- [1- (1- (4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide Methyl-1H
imidazole-4-sulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- (1- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (1-Dimethylsulfamoyl-piperidin-2-ylmethyl) -piperazine-1-carboxylic acid, 4- [1- (2,2,2-HCl) 4- [4- (5-cyclohexyl-2-methoxy-phenyl) thiazol-2-yl] -amide;
Trifluoro-ethanesulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- [1- (4- (4- (4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;
methoxy benzenesulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- [4- (5-Cyclopentyl-2-ethoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-yl) -piperazine-1-carboxylic acid, 4- [1- (3,5-bis (4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;
dimethyl isoxazole-4-sulfonyl) -piperidin-2-ylmethyl] -piperazine-1-carboxylic acid, 4- (5-Butyl-2-ethoxy-phenyl) -thiazol-2-yl] -amide of 4- (Tetrahydro-) pyran-4-yl) -piperazine-1-carboxylic acid, [4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4 - [(S) -1- (1-methyl 1H-imidazole-4-sulfonyl) -piperidin-3-ylmethyl] -piperazine-1-carboxylic acid, 4- (5-Cyclohexyl-2-ethoxy-phenyl) -thiazol-2-yl] -amide of 4- (Tetrahydro-) pyran 4-yl) - piperazine-1-carboxylic acid, 4- [4- (5-Cyclopentyl-2-methoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-yl) -piperazine-1-carboxylic acid, 4- (5-Butyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (Tetrahydro-) pyran-4-yl) -piperazine-1-carboxylic acid, 4- (2-Methoxy-5-propoxyphenyl) thiazol-2-yl] -amide of 4- (Tetrahydro-pyran 4-yl) -piperazine-1-carboxylic acid, 4- (5-propyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (Tetrahydro-) pyran 4-yl) -piperazine-1-carboxylic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-pyran-4-yl) - [1,4] diazepane-1-carboxylic acid. 16. A compound according to any one of claims 1 to 6, characterized in that that R3 represents a group of formula - (CH2) aC where a represents 1, 2, 3 or 4, and C is selected from the group consisting of:

where R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R2, Y and p are as defined in claim 1. 17. A compound according to any one of claims 1 to 6, characterized in that that R3 represents a group of formula -CO (CH2) bC where b represents 0, 1, 2, 3 or 4, and C is selected from the group consisting of:

where R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R2, Y and p are as defined in claim 1. 18. A compound according to any one of claims 1 to 6, characterized in that that R3 represents a group -D in which D is selected in the group consisting of :

where R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R2, Y and p are as defined previously. 19. Compounds according to any one of claims 16 to 18, chosen from :
4- (1,1-Dioxo) 4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide hexahydro-1.lambda.6-thiopyran-4-yl) -piperazine-1-carboxylic acid, 4- (4-Hydroxy) 4- [4- (5-cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;

cyclohexyl) -piperazine-1-carboxylic acid, 4- (1,2,2,6,6-) 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide;

Pentamethyl-piperidin-4-yl) -piperazine-1-carboxylic acid, 4- (2-Cyclohexyl-2-methoxy-phenyl) thiazol-2-yl] -amide of Tetramethyl-piperidin-4-yl) -piperazine-1-carboxylic acid, 4- (2-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide of 4- (2,2-Dimethyl-tetrahydro-pyran-4-ylmethyl) -piperazine-1-carboxylic acid, 4- [4- (5-Cyclohexyl-2-methoxy-phenyl) -thiazol-2-yl] -amide acid (tetrahydro-thiopyran-4-yl) -piperazine-1-carboxylic acid. 20. Process for the preparation of a compound of formula (I) according to any one of of the Claims 1 to 19, comprising the step of reacting a compound of formula (II) with an amine derivative of formula (III) in which R1, R2, Y, R3 and p are as defined in the claim 1 and R'3 represents a precursor group of R3 or a group R3 as defined in the claim 1, in the presence of a coupling agent and in a solvent such as the dichloromethane, dimethylformamide, toluene, in the presence of a base such that triethylamine, K2CO3, at a temperature ranging from 0 ° C to 100 ° C. 21. Process for the preparation of a compound of formula (I) according to any one of of the Claims 1 to 19, comprising the step of reacting a compound of formula (IX), wherein R1, R2, Y, R3 and p are as defined in claim 1, with a compound of formula (V.1) or (V.2) or (VI.1) or (VI.2) or (VII.1) or (VII.2) or a ketone B 'or D', in which a and b are such that defined in claim 1, and A ', B', C 'and D' respectively represent a group precursor of A, B, C, or D, or a group A, B, C or D as defined in the claim 1, to obtain a compound of formula (I) wherein R'3 represents a group precursor of R3 or a group R3 as defined in claim 1. 22. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 19, or an addition salt thereof at a pharmaceutically acceptable acid, or a hydrate or a solvate of compound of formula (I). 23. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 19, or a salt a pharmaceutically acceptable salt, a hydrate or a solvate thereof, and at least one pharmaceutically acceptable excipent. 24. Use of a compound of formula (I) according to any one of claims 1 to 19 for the preparation of a medicament for treatment or to the prevention of acute and severe immuno-inflammatory diseases and syndromes chronic diseases, such as atherosclerosis, allergic diseases and diseases in which angiogenic processes are involved. 25. Use of a compound of formula (I) according to claim 24 for the preparation of a medicament for the treatment or prevention of cancers in which the angiogenic processes are involved. 26. Use of a compound of formula (I) according to any one of claims 1 to 19 for the preparation of a medicament for treatment or prevention of viral or bacterial diseases, pathologies heart, obesity. 27. Use of a compound of formula (I) according to any one of claims 1 to 19 for the preparation of a medicament for treatment or prevention of diseases related to modulation of receptor activity CCR2b.